Type 2 diabetes (T2D) is a major cause of morbidity and mortality in the USA and worldwide. While disease prevalence varies with age, sex, and population, it is estimated that in 2002, 18 million Americans (8.7%) of age =20 years and 8.6 million Americans (18.3%) of age =60 years suffered from T2D. Similar rates of T2D have been observed in Finland. The incidence and prevalence of T2D are increasing in the USA and worldwide. In the USA alone, it is estimated that medical expenditures due to diabetes totaled $132 billion in 2002, ~10% of all USA health care costs. The increasing number of younger T2D cases, including adolescents and children, amplifies the socioeconomic impact of T2D and increases the urgency with which we must act to identify its causes and new treatments. There is substantial evidence of a genetic component in the etiology of T2D and T2D-related traits. The goal of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genetic variants that predispose to T2D and that are responsible for variability in T2D-related quantitative traits. Improved understanding of the genetic basis of T2D and T2D-related traits has the potential to reduce the impact of the current T2D epidemic by supporting identification of novel drugs and therapies, enabling better targeting of preventive and therapeutic approaches, and providing more accurate T2D risk prediction. In this proposal, we seek to build on our successes of the last five years, and particularly the initial findings of our genome-wide association study of T2D in ~2,400 Finnish subjects. Specifically, we will (1) increase substantially our available sample of well-phenotyped study subjects, (2) obtain tissue samples for functional assays on a extensively studied subset of our FUSION study subjects, (3) continue and expand on our current genomewide analyses to identify additional T2D and T2D-related-trait loci by using our existing Finnish samples, samples newly-obtained during this project period, and continued joint and/or meta-analysis with collaborators, (4) fine map and identify predisposing variants in the T2D loci we have discovered or will discover, and assess the allelic spectrum of relevant variants including the possible effects of copy number variants and rare alleles, and (5) assess the predictive power of identified T2D genetic variants in conjunction with other genetic and environmental factors. These efforts will contribute to improved understanding of the etiology of T2D, and have the potential to point the way to novel methods of treatment and prevention. Methods developed and lessons learned in this study will be useful in the study of other complex genetic diseases.